NZ298846A - Valaciclovir tablets containing colloidal silicon dioxide - Google Patents

Description

[page now $ VALACICLOVIR TABLETS CONTAINING COLLOIDAL SILICON DIOXIDE % This invention relates to a tablet of^ the antiviral drug valaciclovir.

The compound 9-[(2-hydroxyethoxy)nfethyl]guanine, otherwise known as acyclovir possesses potent antiviral activity and is widely used in the treatment//and prophylaxis of viral infections in humans, particularly infections caused by the /' herpes group of viruses (see/.for example, Schaeffer et al, Nature, 272, 583-585 (1978)/UK Patent No. 1523865, US Patent No. 4,199,574). However, /acyclovir is poorly absorbed from / / the gastrointestinal traczt''upon oral administration and this low bioavailability meauis that multiple high doses of oral drug may need to be administered, especially for the treatment of less sensitive vi/ruses or infections in order to achieve and maintain effec^iye anti-viral levels in the plasma.

The L-valine estex of acyclovir (2-[2-amino-l, 6-dihydro-6-oxo-purin-9yl)methe>xy]ethyl L-valinate (herein referred to as valaciclovir)/ has been shown to possess much improved bioavailability whilst retaining the anti-viral properties of acyclovir. / / A preferred form of this compound is its hydrochloride salt which is herein referred to as valaciclovir hydrochloride. Valaciclovir and its salts including the hydrochloride salt are disclosed in US Patent No. 4,957,924 (see particular example IB), European Patent No. 0308065 (see particularly example IB) and Beauchamp et al. Antiviral Chsimistry and Chemotherapy, 3(3), 157-164 (1992) (see irticularly page 162 column 1). Tablets of valaciclovir are ilso generally disclosed in the US Patent No. 4,957,924 and European Patent No. 0308065.

PAGE AS AMENDED VAUkCICLOVIR TABLETS CONTAINING COLLOIDAL SILICON DIOXIDE This invention relates to a tablet of the antiviral drug valaciclovir.

The compound 9-[(2-hyaroxyethoxy)methyl]guanine, otherwise known as acyclovir,possesses potent antiviral activity and is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses (see, for example, Schaeffer et al, Nature, 272, 583-585 (1978), UK Patent No. 1523865, US Patent No. 4,199,574). However, acyclovir is poorly absorbed from the gastrointestinal tract upon oral administration and this low bioavailability means that multiple high doses of oral drug may need to be administered, especially for the treatment of less sensitive viruses or infections in order to achieve and maintain effective anti-viral levels in the plasma.

The L-valine ester of acyclovir (2-[ (2-amino-l,6-dihydro-6-oxo-purin-9-yl)methoxy]ethyl L-valinate) (herein referred to as valaciclovir) has been shown to possess much improved bioavailability whilst retaining the anti-viral properties of acyclovir. A preferred form of this compound is its hydrochloride salt which is herein referred to as valaciclovir hydrochloride. Valaciclovir and its salts including the hydrochloride salt are disclosed in US Patent No. 4,957,924 (see particular example IB), European Patent No. 0308065 (see particularly example IB) and Beauchamp et al, Antiviral Chemistry and Chemotherapy, 3(3), 157-164 (1992) (see particularly page 162 column 1). Tablets of valaciclovir are also generally disclosed in the US Patent No. 4,957,924 and European Patent No. 0308065.

Durir.g development of a tablet formulation containing a high proportion of valaciclovir, we often encountered difficulties in obtaining tablets of sufficient hardness and friability for pharmaceutical handling and for film coating.

If the tablet is too friable, it will chip or break during packaging and transport. The US Pharmacopoeia (US?) no. 23, 1995, pi981 at monograph 1216 requires that pharmaceutical tablets have a friability not exceeding 1%. If the tablet is 10 too soft, it will crumble during, tumbling in the film coating pan.

* In the reference manual 'Problem Solver' (compiled by FMC Corporation) at pages 8 and 9, the remedies for low tablet 15 hardness are given Inter alia as increasing the compression force applied to form the tablet, or decreasing the proportion of lubricant in the tablet formulation.

We tried to increase the hardness and friability of 20 valaciclovir tablets by increasing the compression force, by decreasing the proportion of lubricant and increasing the proportion of binder, but found in each case that a sufficiently hard and non-friable tablet could not be produced in a practical way.

Furthermore, cracks were found in some tablets as a result of increasing the compression force. Additionally, valaciclovir has 'adhesive' properties in that it can stick to tablet dies and therefore needs to be efficiently lubricated. It is 30 difficult therefore to reduce the proportion of lubricant without causing the tablets to stick. Furthermore, the disintegration time of the valaciclovir tablet is also quite long and therefore any possible solution to the hardness and friability problem should not have a substantial deleterious 23 effect on either the disintegration time or lubrication (as -assured tv the ejection force) of the tablet formulation.

AGE NOW AME % . ~ is therefore an cbiec- of the invention to provide/a robust tablet formulation of valaciclovir and salts thereof which is capable of being film coated and consistently providing tablets having a friability not exceeding 1,%, &. hardness of at least 9k? and an ejection force not exceedi/g 1000 Newtons (1 kN).

The hardness of the tablet should be such /hat it not only has an acceptable crushing force (as measured by the kP value), but also that the tablet does not breax during tumbling.

It is a further preferred object of/the invention to provide a robust formulation which is/ capable of consistently providing tablets substantially/free of cracks.

We have now found an effectiyfe method of overcoming both of the above friability and hardness problems which involves the extragranular use of colloidal silicon dioxide and cellulosic filler in th/e tablet formulation.

The Handbook of Pharmaceutical Excipients 1994 at p253~256 does not mention colloidal silicon dioxide as an agent to improve the hardnesspt tablets. Neither does The Theory and Practice of Industr/al Pharmacy (third edition) by Lachman, Lleberman and Kan/cr, mention colloidal silicon dioxide for such a use.

Accordingly ii/ a first aspect of the invention there is provided a /tablet comprising at least about 50% w/w 30 valacicloviir or a salt thereof present within the granules or the tablet, a cellulosic filler, a binding agent, a lubricant, and about 0.05% to about 3% w/w colloidal silicon/ dioxide, the lubricant, colloidal silicon dioxide and at least a portion of the cellulosic filler beingf present extragranularly, wherein the friability of the/tablet does not exceed 1%, the hardness is at least and the ejection force does not exceed 1000 Newtons.

PAGE AS AMENDED It is therefore an object of the invention to provide a robust tablet formulation of valaciclovir and salts thereof which is capable of being film coated and consistently providing tablets having a friability not exceeding 1%, a hardness of at least 9kP and an ejection force not exceeding 1000 Newtons (1 kN) .

The hardness of the tablet should be such that it not only has an acceptable crushing force (as measured by the kP value), but also that the tablet does not break during tumbling.

It is a further preferred object of the invention to provide a robust formulation which is capable of consistently providing tablets substantially free of cracks.

We have now found an effective method of overcoming both of the above friability and hardness problems which involves the extragranular use of colloidal silicon dioxide and cellulosic filler in the tablet formulation.

The Handbook of Pharmaceutical Excipients 1994 at p253-256 does not mention colloidal silicon dioxide as an agent to improve the hardness of tablets. Neither does The Theory and Practice of Industrial Pharmacy (third edition) by Lachman, Lieberman and Kanig, mention colloidal silicon dioxide for such a use.

Accordingly in a first aspect of the invention there is provided a tablet comprising at least about 50% w/w valaciclovir or a salt thereof present within the granules of the tablet, a cellulosic filler, a binding agent, a lubricant, and about 0.05% to about 3% w/w colloidal silicon dioxide, the lubricant, colloidal silicon dioxide and at least a portion of the cellulosic filler being present extragranularly, wherein the friability of the tablet does not exceed 1%, the hardness is at least 9kP and the ejectioi exceed 1000 Newtons.

OFFICE OF N.Z. 7 mar 2001 wo PCT/GB96/00! 11 "4" (£Q; O V'C Wy M/j A tablet of this formulation containing 0.05% to 3% yr-colloidal silicon dioxide and a cellulosic fiMer is robust, and has a substantially improved friability and hardness. Furthermore such improved 5 properties is achieved while still retaining a satisfactory disintegration time and lubrication properties, evjsn when the // formulation is blended under high shear. An excellent tablet providing acyclovir in a highly bioavaiiable/f orm is thus provided by virtue of the invention.

•Q) / Preferably the disintegration time of the/tablet is not more than about 30 minutes, more preferably njpt more than about 25 minutes, and most preferably not mor=/than about 20 minutes.

//' The ejection force should net more than about 1000N, 7/ preferably not more than about 80&N, more preferably still not more than about 500N for tablets' compressed at about 10 to 30 / / kN, preferably 10 to 20 kN.

Valaciclovir or a salt thereof are hereinafter referred to generally as the ' activ^ingredient1 .

The 19S4 U.S. Pharmacopoeia describes colloidal silicon 25 dioxide (in its monograph) as: a submicroscopic fumed silica prepared by the vapour phase hydrolysis of a silica compound.

Preferably the /olloidal silicon dioxide is present in amounts / ^ of about 0.05#:* to about 1% w/w of the total formulation, more /1' preferably a/t about 0. 1% to about 1% w/w, and most preferably // about 0.1%^-to about 0.5% w/w. We have found Aerosil (trade mark) and^Cab-o-sil (trade mark) to be very suitable.

The cortent of drug in the tablet is at least about 50% w/w, preferably about 60% w/w to about 90% w/w., more preferably sti/l about 65% w/w to about 85% w/w and most preferably about w/w. Preferably the (tapped) bulk density of the drug is feout 0.1 to 0.9 g/cc, more preferably 0.3 to 0.7 g/cc, more PAGE AS AMENDED 298846 A tablet of this formulation containing 0.05% to 3% w/w colloidal silicon dioxide and a cellulosic filler is robust, and has a substantially improved friability and hardness. Furthermore such improved properties is achieved while still retaining a satisfactory disintegration time and lubrication properties, even when the formulation is blended under high shear. An excellent tablet providing acyclovir in a highly bioavailable form is thus provided by virtue of the invention.

Preferably the disintegration time of the tablet is not more than about 30 minutes, more preferably not more than about 25 minutes, and most preferably not more than about 20 minutes.

The ejection force should not be more than about 1000N, preferably not more than about 800N, more preferably still not more than about 500N for tablets compressed at about 10 to 30 kN, preferably 10 to 20 kN.

Valaciclovir or a salt thereof are hereinafter referred to generally as the 'active ingredient' or 'drug' .

The 1994 U.S. Pharmacopoeia described colloidal silicon dioxide (in its monograph) as: a submicroscopic fumed silica prepared by the vapour phase hydrolysis of a silica compound.

Preferably the colloidal silicon dioxide is present in amounts of about 0.05% to about 1% w/w of the total formulation, more preferably at about 0.1% to about 1% w/w, and most preferably about 0.1% to about 0.5% w/w. We have found Aerosil (trade mark) and Cab-o-sil (trade mark) to be very suitable.

The content of drug in the tablet is at least about 50% w/w, preferably about 60% w/w to about 90% w/w, more preferably still about 65% w/w to about 85% w/w and most preferably about 80% w/w. Preferably the (tapped) bulk density of the drug is about 0.1 to 0.9 g/cc, more preferably 0.3 to i.QxETj.EgVtG'o;. .pRmec&eY OFFICE OF N.Z. " 7 mar 2001 K E C SII ¥ E B # PAGE NOW AMENDED] PCT/GB96/00M1 'f (/ preferably still 0.34 to 0.66 g/cc, and most px^Sferably 0.4 to 0.6g/cc. Suitably the drug is valaciclovir hydrochloride, preferably being of an anhydrous crystalling/form including substantially a d-spacing pattern (derivedyrrom X-ray powder diffraction) as follows: d spacing pattern (in Angstroms): .20 ± 0.08, 8.10 ± 0.06, 7.27 ±/Q.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4y69 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± Q.&2, 3.32 ± 0.02, 2.91 ± 0.02, 2.77 ±,0.02.

Hereinafter by "anhydrous Crystalline form" according to the / / invention, we mean a crystalline form having substantially the same X-ray powder diffraction pattern as shown in figures 1 to 3, or having substantially the same d spacing pattern as defined above.

// Preferably the crystal form purity in any such drug lot of anhydrous crystalline valaciclovir hydrochloride used for valaciclovir -tablets is as least 70%, more preferably at least 80%, more preferably still at least 90% and most preferably at least 9 5Sf ^anhydrous crystalline valaciclovir hydrochloride (as characterised above). ternative method for measuring crystal form purity, / the In an / / since / /the anhydrous crystalline form of valaciclovir hydrochloride contains substantially no water of hydration, 30 the/ /level of other hydrated forms of valaciclovir hydrochloride in any drug lot used for tablets can be measured the water of hydration content. Preferably any such drug of anhydrous crystalline valaciclovir hydrochloride Contains no more than 3% w/w, more preferably no more than 2% w/w, more preferably still not more than 1 % w/w and most preferably not more than 0. 5 % w/w water of hydration. 'lot ASM3ENI preferably still 0.34 to 0.66 g/cc, and most preferably 0.4 to 0.6g/cc. Suitably the drug is valaciclovir hydrochloride, preferably being of an anhydrous crystalline form including substantially a d-spacing pattern (derived from X-ray powder diffraction) as follows: d spacing pattern (in Angstroms): .20 ± 0.08, 8.10 -± 0.06, 7.27 ± 0.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02, 2.77 ± 0.02.

Hereinafter by "anhydrous crystalline form" according to the invention, we mean a crystalline form having substantially the same X-ray powder diffraction pattern as shown in figures 1 to 3, or having substantially the same d spacing pattern as de fined above.

Preferably the crystal form purity in any such drug lot of anhydrous crystalline valaciclovir hydrochloride used for valaciclovir tablets is as least 70%, more preferably at least 80%, more preferably still at least 90% and most preferably at least 95% anhydrous crystalline valaciclovir hydrochloride (as characterised above).

In an alternative method for measuring crystal form purity, since the anhydrous crystalline form of valaciclovir hydrochloride contains substantially no water of hydration, the level of other hydrated forms of valaciclovir hydrochloride in any drug lot used for tablets can be measured by the water of hydration content. Preferably any such drug lot of anhydrous crystalline valaciclovir hydrochloride contains no more than 3% w/w, more preferably no more than 2% w/w, more preferably still not more than 1 % w/w and most preferably not more than 0. 5 % w/w water of jriySg^?i6nffR°2";'oY " 7 mar 2001 is i? p. £ n u f Pi WO 96/22082- #• PAGE NOW ■ o- This water cf hydration content is measured by the Karl Fischer method which is well known in the art and is described / / tne 19S0 U.S. Pharmacopoeia at pages 1619-1621, and: the European Pharmacopoeia, second edition ( 1 992),y^dirt 2, sixteenth fasicule at v. 3.5.6-1.

The cellulosic filler is at leas»i /f // partly- present extragranularly, which mitigates stress */ cracking of the tablet. A tablet formulatioxyof the invention J7 including colloidal silicon dioxide (^and extragranular cellulosic filler (such as micrccrYStalline cellulose) appears to have a synergistic effect and is particularly good ar.d robust in that tablets of valaciclovir can consistently be made to an acceptable hardness sfithout introducing stress cracks even under a high compression force.

According to a preferred aspect of the invention there is provided a tablet comprising''at least 50% w/w valaciclovir or a salt thereof, a binding/agent, a lubricant, 0.05 to 3% w/w 20 colloidal silicon dioxide, and 3 to 30% of a cellulosic filler; wherein the vadaciclovir or salt thereof is present within the granules pz the tablet, the lubricant, colloidal /f silicon dioxide, and at least a portion of the cellulosic filler is present/'extragranularly; wherein the friability of 25 the tablet does/not exceed 1%, the hardness is at least 9kP, and the ejection force does not exceed 1000N.

Preferably// the cellulosic filler is microcrystalline // cellulosavte.g. Avicel); and is preferably present at 5 to 15% // -30 w/w, rno^t preferably about 10% w/w. The particle size of the cellurosic filler is preferably 20 to 300p, more preferably Xjb' 20Qp, and most preferably 50 to lOOji. /eccrair to a further aspect of the invention there is 35 /provided a tablet comprising at least 50% w/w valaciclovir or a salt thereof, a binding agent, a lubricant, and about 3% to PAGE AS AMEMDEO 2988 4 This water of hydration content is measured by the Karl Fischer method which is well known in the art and is described in the 1990 U.S. Pharmacopoeia at pages 1619-1621, and the European Pharmacopoeia, second edition (1 992), part 2, sixteenth fasicule at v. 3.5.6-1.

The cellulosic filler is at least partly present extragranularly, which mitigates stress cracking of the tablet. A tablet formulation of the invention including 10 colloidal silicon dioxide and extragranular cellulosic filler (such as microcrystalline cellulose) appears to have a synergistic effect and is particularly good and robust in that tablets of valaciclovir can consistently be made to an acceptable hardness without introducing stress cracks even 15 under a high compression force.

J According to a preferred aspect of the invention there is provided a tablet comprising at least 50% w/w valaciclovir or a salt thereof, a binding agent, a lubricant, 0.05 to 3% w/w 20 colloidal silicon dioxide, and 3 to 30% of a cellulosic filler; wherein the valaciclovir or salt thereof is present within the granules of the tablet, the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic filler is present extragranularly; wherein the friability of 25 the tablet does not exceed 1%, the hardness is at least 9kP, and the ejection force does not exceed 1000N.

Preferably the cellulosic filler is microcrystalline cellulose (e.g. Avicel); and is preferably present at 5 to 15% w/w, most 30 • preferably about 10% w/w. The particle size of the cellulosic filler is preferably 20 to 300/u, more preferably 30 to 200/u, and most preferably 50 to lOO^i.

INTELLECTUAL PROP-RlY OFFICE OF N.Z. " 7 mar 2001 wo 06,21'js: PCT/GBVo/OO 11 i PAGE NOW AMENDED C-). % w/w cf a cellulosic filler, the vala: being present within the granules cf t lubricant and cellulosic filler extragranularly. f ti he table- ani1/ the oamg The binding agent serves, for example, to bind ths / . primarv and secondary particles together and improve tzpflajt hardness.

/ // Preferably the binding agent is present in an/amount of about / ^ 1% to about 5% w/w, more preferably at about/2% to about 4% / / w/w, and is suitably a non-starch based /binder such as / methvlcellulose or most oreferablv ccv/dohe. 'he grade of povidone is advantageously K3Q and mo/t preferably K9( The binding agent such as the povicone, can be dissolved in the granulating solvent (such as /atef) before adding to the drug, but preferably it is added/(at/least partly) dry to the drug and other excipients and/then' the granulating solution (such as povidone in water) The lubricant is suitably /present in an amount of about 0.1% to about 2.0% w/w, preferably about 0.1% to about 1.0% w/w. Although lubricants suc^ as talc or sodium iauryl sulphate are suitable, preferably Vhe lubricant is a stearate derivative/ more preferably an/alkaline earth metal stearate, such as magnesium stearate. The above amounts apply to the stearate, and Uley are ideally present in amount of at about 0.3% to /&bout 0.6% w/w.

: Although vala6/clovir is very soluble, especially in its sal_ form, it is/preferable if a disintegrating agent is present // in the tabYet formulation, suitably in an amount of about O.o // to aoout//0% w/w, more preferably at about 0.5% to 7.0% w/w.

The disintegrating agent is advantageously present within the granules of the tablet and can be added before or after the binding, agent. Clays such as kaolin, bentor.ite or veegum // (trademark), and celluloses such as microcrvstailine cellulose PAGE AS AMENDED 298846 The binding agent serves, for example, to bind the primary and secondary particles together and improve tablet hardness. Preferably the binding agent is present in an amount of about 1% to about 5% w/w, more preferably at about 2% to about 4% w/w, and is suitably a non-starch based binder such as methylcellulose or most preferably povidone. The grade of povidone is advantageously K30 and most preferably K90.

The binding agent such as the povidone, can be dissolved in the granulating solvent (such as water) before adding to the drug, but preferably it is added (at least partly) dry to the drug and other excipients and then the granulating solution (such as povidone in water) added.

The lubricant is suitably present in an amount of about 0.1% to about 2.0% w/w, preferably about 0.1% to about 1.0% w/w. Although lubricants such as talc or sodium lauryl sulphate are suitable, preferably the lubricant is a stearate derivative, more preferably an alkaline earth metal stearate, such as magnesium stearate. The above amounts apply to the stearate, and they are ideally present in amount of at about 0.3% to about 0.6% w/w.

Although valaciclovir is very soluble, especially in its salt form, it is preferable if a disintegrating agent is present in the tablet formulation, suitably in an amount of about 0.5 to about 20% w/w, more preferably at about 0.5% to 7.0% w/w. The disintegrating agent is advantageously present within the granules of the tablet and can be added before or after the binding agent. Clays such as kaolin, bentonite or Veegum (trademark), and celluloses such as microcrystalline cellulose INTELLECTUAL PROPERTY OFFICE OF N.Z. " 7 mar 2001 RE& n, I \J ZD or croscarmellose sodium e.g. Ac-Di-Sol (trademark) maybe used as disintegrants. Preferably a non-ionic disintegrant such as crospovidone is used. Preferably, the crospovidone is present at about 0.5% to about 7.0% w/w, more preferably about 2 to about 5% w/w, and preferably a portion is present intragranularly.

A further aspect of the invention provides a process for preparing a tablet comprising at least about 50% w/w valiclovir or a salt thereof, a binding agent, cellulosic filler, a lubricant, and about 0.05 to 3.0% w/w colloidal silicon dioxide; wherein the hardness of the tablet is at least 9 kP, the friability is not more than 1%, and the ejection force is not more than 1000N; said process comprising forming granules which include valaciclovir or a salt thereof, then blending the lubricant, colloidal silicon dioxide and at least a portion of the cellulosic filler with said granules, and then compressing the blended mixture to form a tablet.

Preferably said process comprises forming granules by mixing said valaciclovir or salt, optionally a binding agent or a portion thereof, and optionally a portion of the cellulosic filler; granulating with a granulating solution to form granules or dissolving the binding agent or a portion in the granulating solution before adding to valaciclovir; drying the granules; blending the granules with the lubricant, colloidal silicon dioxide, and cellulosic filler or a portion thereof; and then compressing the blended mixture to form a tablet.

A preferred aspect of the invention provides a process for preparing a tablet comprising at least 50% w/w valaciclovir or a salt thereof, a binding agent, a lubricant, 0.05 to 3% w/w colloidal silicon dioxide, and 3 to 30% w/w of a cellulosic filler; wherein the hardness cf the tablet is at least 9kP, the friability is not more than 1%, and the ejection force is not more than 1000N; said process comprising forcing granules by mixing the valaciclovir or salt, optional •§ | PAGE NOW AMENDED] 2 V '/ binding agent or a portion thereof, and optionally a -portion / y of cellulosic filler; granulating with a granulatinc/sqlution to form granules or dissolving the binding agent qt a/'portion thereof in the granulating solution before/ adding to valaciclovir; drying the granules; blending the/granules with the lubricant, colloidal silicon dioxide, /and/at least a / / portion of the cellulosic filler; and then compressing the blended mixture to form a tablet. / / / The colloidal silicon dioxide can be #irs;t: blended with the lubricant, preferably a stearate derivative (e.g. magnesium stearate) before blending with the g/anules or it can be added / 7 separately from the lubricant. /When the lubricant is a stearate derivative, preferably/ the ratio of stearate to colloidal silicon dioxide is/ aBout 1:1 to 10:1, more preferable about 1: I to about/3: 1.

The present invention also /provides a tablet (as described above) for use in medical therapy, e.g. in the treatment of 20 a viral disease in an animal, e.g. a mammal such as a human. The compound is espec/ally useful for the treatment of diseases caused by various DNA viruses , such as herpes infections, for example, herpes simplex 1 and 2, varicella ■. zoster, cytomegalovirus, Epstein-Barr viruses or human herpes 25 virus-5 (HHV-6) as/well as diseases caused by hepatitis B. The active compound/ can also be used for the treatment of papilloma or w/rt virus infections and, may furthermore be administered i/n combination with other therapeutic agents, for example with zidovudine, to treat retroviral associated 30 infections/in particular KIV infections.

In addition to its use in human medical therapy, the active compound can be administered to other animals for treatment of /iral diseases, e.g. to other mammals.

PAGE AS AMENDED binding agent or a portion thereof, and optionally a portion of cellulosic filler; granulating with a granulating solution to form granules or dissolving the binding agent or a portion thereof in the granulating solution before adding to valaciclovir; drying the granules; blending the granules with the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic filler; and then compressing the blended mixture to form a tablet.

The colloidal silicon dioxide can be first blended with the lubricant, preferably a stearate derivative (e.g. magnesium stearate) before blending with the granules or it can be added separately from the lubricant. When the lubricant is a stearate derivative, preferably the ratio of stearate to colloidal silicon dioxide is about 1:1 to 10:1, more preferable about 1:1 to about 3:1.

The present invention also provides a tablet (as described above) for use in medical therapy, e.g. in the treatment of a viral disease in an animal, e.g. a mammal such as a human. The compound is especially useful for the treatment of diseases caused by various DNA viruses, such as herpes infections, for example, herpes simplex 1 and 2, varicella zoster, cytomegalovirus, Epstein-Barr viruses or human herpes virus-6 (HHV-6) as well as diseases caused by hepatitis B. The active compound can also be used for the treatment of papilloma or wart virus infections and, may furthermore be administered in combination with other therapeutic agents, for example with zidovudine, to treat retroviral associated infections in particular HIV infections.

In addition to its use in human medical therapy, the active compound can be administered to other animals for treatment of viral diseases, e.g. to other mammals.

INTELLECTUAL PROPERTY I OFFICE OF N.Z. " 7 mar 2001 PAGE IENDED The present tablet also provides a method for the/treatment of a viral infection, particularly a herpes viral/Infection, f/ in an animal, e.g. a mammal such as a human, whi^h comprises / / administering to the host one or more tablets of/the invention to provide an effective antiviral amounV/of the active compound.

The present invention also provides -thM use of the active compound in the preparation of a tabley of the invention for the treatment of a viral infection.

A tablet of the invention may be/administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral/ Although tablets generally are included within the scope/of the invention, for example a dispersible tablet or chewaple tablet, preferably the tablet is a swallowable tablet,/ most preferably a film-coated swallowable tablet. It wid.1 be appreciated however, that the preferred route may varj^fwith, for example, the condition of the recipient.

For each of the above^indicated utilities and indications the amounts required ofythe active ingredient (as above defined) will depend upon M number of factors including the severity // of the condition to be treated and the identity of the /{ recipient and will ultimately be at the discretion of the /i attendant physacian or veterinarian. In general however, for // each of these//utilities and indications, a suitable effective dose will bp in the range 1 to 150 mg per kilogram bodyweight 30 of recipient per day, preferably in the range 5 to 120 mg per kilogram/bodyweight per day (Unless otherwise indicated, all weights/of the active ingredient are calculated with respect to th/e free base valaciclovir). The desired dose is preferably presented as one, two, three or four or more sub-35 dos>/s administered at appropriate intervals throughout the d&y. These sub-doses may be administered in unit dosage »AGE AS AMI & o o o ^ The present invention also provides the use of the active compound in the preparation of a tablet of the invention for the treatment of a viral infection.

A tablet of the invention may be administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral. Although tablets generally are included within the scope of the invention, for example a dispersible tablet or chewable tablet, preferably the tablet is a swallowable tablet, most preferably a film-coated swallowable tablet. It will be appreciated however, that the preferred route may vary with, for example, the condition of the recipient.

For each of the above-indicated utilities and indications the amounts required of the active ingredient (as above defined) will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician or veterinarian. In general however, for each of these utilities and indications, a suitable effective dose will be in the range 1 to 150 mg per kilogram bodyweight of recipient per day, preferably in the range 5 to 120 mg per kilogram bodyweight per day (Unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base valaciclovir). The desired dose is preferably presented as one, two, three or four or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage IKTELLECTUAL PROPERTY OFFICE OF N.Z. ~ 7 mar 2001 RECCED forms, for example, containing about 50 to 2000 mg, preferably about 250, 500, 1000 or 2000 mg of active ingredient per unit dose form.

The following dosage regimes are given for guidance: treatment of herpes simplex virus types 1 and 2 infection:-total daily dose of about 1 or 2g administered at 500mg twice a day or lg twice a day for 5 to 10 days; suppression of herpes simplex virus types 1 and 2 infections:- total daily dose about 250mg to lg for about one to ten years (depending on the patient); treatment of varicella zoster virus infections (for example shingles)daily dose about 3g administered at lg three times a day for seven days; suppression of cytomegalovirus infections-.- total daily dose about 8g administered at 2g 4 times a day. For transplant patients this daily dose is administered for three to six months for the period at risk; and for HIV positive patients said daily dose is administered as usually indicated for improving quality of life, for example for two years or more.

Early results now indicate that valaciclovir can be used in the effective suppression of recurrent genital herpes at a once daily dose of from about 200 mg to about 1000 mg for an effective treatment period. The most likely daily dosages are 250 mg, 500 mg or 1000 mg.

Valaciclovir hydrochloride was made as described below: Example 1 A. 2-T(2-amino-l.6-dihydro-6-oxo-9H-purin-Yl) methoxylethvl-N- \ (benzyloxycarbonyll-L-valinate CBZ-L-valine (170 g) was dissolved in dimethylformamide (DMF) (750 ml) and cooled. A cold solution of N,N-dicyclo-hexyl-carbodiimide (DCC) (156.7g) in DMF (266 ml) was added and stirred with cooling. Acyclovir (10.1 g) was added in a single portion, and then 4-(dimethylamino) pyridine (9.4 g) was added while maintaining cooling. The mixture was stirred cold overnight. A white WO 96/22082 PCT/GB96/00111 precipitate of the by-product was then removed by filtration. The filtrate was reduced in volume by vacuum distillation and the concentrate treated with water (663 ml) then heated to 70°C. The suspension was cooled to 20#C, filtered and the solid washed with water.

The damp, crude material was then purified by recrystallisation from denatured alcohol (1.2 litres) to afford the title compound as a damp white crystalline solid (281.5 g).

B. 2-T(2-amino-l.6-dihvdro-6-oxo-9H-purin-9-vl) methoxvlethvl-L-valinate hydrochloride 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl-N-[(benzyloxy)carbonyl]-L-valinate (175 g) was charged to aqueous denatured alcohol (335 ml/795 ml) and heated to reflux. The solution was then cooled to 40"C. The suspension was treated with 5% palladium on carbon catalyst (35 g wet weight 50% wet with water) then formic acid (30.6 ml of 90% w/w) added over 1 hour. The reaction mixture was stirred for a further 1 hour then a second charge of formic acid made (19.5 ml) and the mixture filtered to remove the catalyst. The filter cake was washed with denatured alcohol and the combined filtrates were treated with concentrated hydrochloric acid (33.7 ml) and the resultant mixture was concentrated by vacuum distillation.

Acetone (1295 ml) was then added over 15 minutes and the suspension stirred for 1 hour before filtering off the product. The solid was then slurried with acetone (circa. 530 ml), refiltered and dried at 60°C in vacuo to give the title compound (1123 g : 81.6%).

A 15 g sample of this material was combined with denatured alcohol (circa. 7 ml), to moisten and was heated with agitation at 60°C overnight in a closed flask to avoid loss of alcohol and maintain the dampness of the mixture. The mixture was then dried at 60'C In vacuo to afford the product as the desired morphic form.

Physical Data: Karl Fischer value : 0.9% w/w water.

The X-ray powder diffraction patterns of the product of example IB are shown in Figure 1 of the accompanying drawings.

The d spacings and further X-ray diffraction data are shown in Table 1.

•# -AGE NOW AMENDED 40 Table 1 Peak No: I/Imax (%) Angle Peak (degrees) (counts) d Spacing pattern Error in d (± A) (A) 3.56 680 24.8 0.5/ 24 8.62 1151 .25 0y08 39 9.42 87 9.38 Of. 07 3 .86 1438 8.14 AO.06 49 12.10 835 7.31 / 0.06 28 13.22 198 6.69 // 0.05 6 14.49 2172 6.11 A / 0.05 75 .12 455 .85 // 0.03 .90 352 .57 Af 0.02 12 16.45 1969 .38y 0.02 68 16.90 744 .24 0.02 17.33 119 /11 0.02 4 18.12 1013 2289 0.02 22.71 1429 /4.43 0.02 49 .55 256 // 4.32 0.02 8 21.21 370 / / 4.19 0.02 12 21.83 753 // 4.07 0.02 26 22.71 95 // 3.91 0.02 3 23.95 2893 /' 3.71 0.02 100 .10 171 / 3.54 0.02 26.21 1784T' 3.40 0.02 61 26.89 428 3.31 0.02 14 27.08 373 3.29 0.02 12 28.02 /l58 3.18 0.02 28.27 / 161 3.15 0.02 28.91 / 391 3.09 0.02 13 29.68 J " 191 3.01 0.02 6 .55/ 502 2.92 0.02 17 31.3 f 110 2.85 0.02 3 31. SB 98 2.83 0.02 3 32 yi3 597 2.78 0.02 32.96 260 2.72 0.02 8 23.99 344 2.64 0.02 11 34.38 374 2.61 0.02 12 .12 141 2.55 0.02 4 36.78 408 2.44 0.02 14 38.71 101 2.32 0.02 3 I/Imfex = (peak height/max. peak ht) x 100 page as amended Table 1 V 84 : : Peak No: Angle Peak d Spacing Error in I/Imax (degrees) (counts) pattern (A) d (± A) (%) 1 3.56 680 24.8 0.5 24 2 8.62 1151 .25 0.08 39 3 9.42 87 9.38 0.07 3 4 .86 1438 8.14 0.06 49 12.10 835 7.31 0.06 28 6 13.22 198 6.69 0.05 6 7 14.49 2172 6.11 0.05 75 a .12 455 .85 0.03 9 .90 352 .57 0.02 12 16.45 1969 .38 0.02 68 11 16.90 744 .24 0.02 12 17.33 119 .11 0.02 4 13 18.12 1013 4.89 0.02 14 22.71 1429 4.43 0.02 49 .55 256 4.32 0.02 8 16 21.21 370 4.19 0.02 12 17 21.83 753 4.07 0.02 26 18 22.71 95 3.91 0.02 3 19 23.95 2893 3.71 0.02 100 .10 171 3.54 0.02 21 26.21 1784 3.40 0.02 61 22 26.89 428 3.31 0.02 14 23 27.08 373 3.29 0.02 12 24 28.02 158 3.18 0.02 28.27 161 3.15 0.02 26 28.91 391 3.09 0.02 13 27 29.68 191 3.01 0.02 6 28 .55 502 2.92 0.02 17 29 31.34 110 2.85 0.02 3 31.58 98 2.83 0.02 3 31 32.13 597 2.78 0.02 40 32 32.96 260 2.72 0.02 8 33 33.99 344 2.64 0.02 11 34 34.38 374 2.61 0.02 12 .12 141 2.55 0.02 4 36 36.78 408 2.44 0.02 14 45 37 38.71 101 2.32 0.02 INTELLECTUAL PROPERTY I/Imax = (peak height/max. peak ht) x 100 OFFICE OF N.Z. " 7 mar 2001 RE© IV ZB // WO 96/22082- PAGE NOW AMENDED / The powder sample used to produce the above X-ray diffraction data was prepared by an equivalent method as the powder sample used to produce the X-ray diff/action date of table 2 (described hereinafter) exceptyzhat for the above data the following preparation was used/to prepare the powder sample.

The sample was prepared by milling 1 g of/sample in a plastic cup using two acrylic balls for/5 minutes with a Chemplex Spectromill. The samples were then back packed against a glass slide to a depth of mm.

The X-ray diffraction scan was obtained using a Scintag PADV diffractometer in the step scan mode at 0.02° per step 15 and a 10 second count per step.// The sample holder was '/ spun at 1 rotation per second during the scan, setting as described below.

Additional X-ray generator: Radiation: Fixed divergent slit: Incident scatter slil kV, 40 mA 'Copper K alpha radiation 1 mm 2 mm Diffracted scatteryslit: 0.5 mm Receiving slit: / 0.3 mm Goniometer radiufe: 235 mm Detector: /Scintillation with a graphite monochromator.

The peak intensities are reported as absolute counts of the peak top./ The intensity units on the X-ray diffraction 30 plot arj2 counts/sec. The absolute counts = counts/sec x count/time = counts/sec x 10 sec. The peak intensities in the /table have been corrected for background and copper K )ha II X-ray wavelength contribution. page as amended 298846 The powder sample used to produce the above X-ray diffraction data was prepared by an equivalent method as the powder sample used to produce the X-ray diffraction data of table 2 (described hereinafter) except that for the 5 above data the following preparation was used to prepare the powder sample.

The sample was prepared by milling 1 g of sample in a plastic cup using two acrylic balls for 5 minutes with a 10 Chemplex Spectromill. The samples were then back packed against a glass slide to a depth of 2 mm.

The X-ray diffraction scan was obtained using a Scintag PADV diffractometer in the step scan mode at 0.02° per step 15 and a 10 second count per step. The sample holder was spun at 1 rotation per second during the scan. Additional setting as described below.

X-ray generator: 45 kV, 40 mA Radiation: Copper K alpha radiation Fixed divergent slit: 1 mm Incident scatter slit: 2 mm Diffracted scatter slit: 0.5 mm Receiving slit: 0.3 mm Goniometer radius: 235 nun Detector: Scintillation with a graphite monochromator.

The peak intensities are reported as absolute counts of the peak top. The intensity units on the X-ray diffraction 30 plot are counts/sec. The absolute counts = counts/sec x count time = counts/sec x 10 sec. The peak intensities in the table have been corrected for background and copper K alpha II X-ray wavelength contribution.

INTELLECTUAL PROPERTY I OFFICE OF N.Z. I ' 7 mar 2001 nEC E0\7Ein) PAGE Nggp] Example 2 A. 2-T ( 2-amino-l.6-dihvdro-6-oxo-9H-purin-9-vl) methoxylethvl-N-T(benzvloxv)carbonvll-L-valinats , y CBZ-L-valine (167 g) was dissolved in dimethylformamide (DMF) (750 ml) and cooled to 0.5°C. A cold solj^tion of N,N-dicyclohexylcarbodiimide (DCC) (153.5 g) in DMF (266 ml) was added followed by acyclovir (111.7 q4 in a single 10 portion. 4(Dimethylamino)pyridine (9.4 g) /as then added and the mixture stirred cold overnight. /h ;white / y precipitate of the by-product was then/removed by / // filtration. The solvent was partially removed by vacuum distillation and the concentrate treated with water (663 15 ml) then heated to 70°C. The suspension was cooled to 20°C, filtered and the solid warned/ with water.

The damp, crude material was /then purified by recrystallisation from denatured alcohol (1.2 litres) to afford the title compound/as a damp white crystalline solid (215.3 g). / / B. 2-f(2-amino-l.6yaihvdro-6-oxo-9H-purin-9-vl) methoxvlethvl -/L-vallnate hydrochloride / 2-[(2-amino-l,67aihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl- N-[(benzyloxy)(carbonyl]-L-valinate (200 g) was charged to / / aqueous denatured alcohol (382 ml / 908 ml) and heated to / / reflux to dissolve solids. The solution was cooled to / / 40°C. The/suspension was treated with a 50% w/w paste of % palladium on carbon catalyst and water (40 g) then / / formic Acid (96% w/w : 32.8 ml) added over 1 hour. The reaction mixture was stirred for a further 1 hour then a second charge of formic acid made (20.88 ml) and the mi/ture filtered to remove the catalyst. The filtrate was i/t. && r-, // Example 2 A. 2- f C 2-amino-l. 6-dihvdro-6-oxo-9H-purin-9-vl^ methoxylethvl-N- f f benzvloxv) carbonvl 1 -L-valinatP CBZ-L-valine (167 g) was dissolved in dime-thylformamide (DMF) (750 ml) and cooled to 0.5°C. A cold solution of N,N-dicyclohexylcarfaodiimide (DCC) (153.5 g) in DMF (266 ml) was added followed by acyclovir (111.7 g) in a single 10 portion.4-(Dimethylamino)pyridine (9.4 g) was then added and the mixture stirred cold overnight. A white precipitate of the by-product was then removed by filtration. The solvent was partially removed by vacuum distillation and the concentrate treated with water (663 15 ml) then heated to 70°C. The suspension was cooled to 20°C, filtered and the solid washed with water.

The damp, crude material was then purified by recrystallisation from denatured alcohol (1.2 litres) to 20 afford the title compound as a damp white crystalline solid (215.3 g).

' B. 2-f(2-amino-l.6-dlhvdro-6-oxo-9H-purln-9-vl) methoxvlethvl-L-vallnate hydrochloride 2-[(2-amino-l,6-dihyaro-6-oxo-9H-purin-9-yl)methoxy]ethyl-N-[(benzyloxy)carbonyl]-L-valinate (200 g) was charged to aqueous denatured alcohol (382 ml / 908 ml) and heated to reflux to dissolve solids. The solution was cooled to 40 *C. The suspension was treated with a 50% w/w paste of 5% palladium on carbon catalyst and water (40 g) then formic acid (96% w/w : 32.8 ml) added over 1 hour. The reaction mixture was stirred for a further 1 hour then a second charge of formic acid made (20.88 ml) andtii©,- — . ^ J^TPLLICTUALPROP^ mixture filtered to remove the catalyst. The :i iIt¥^|2;EW^ N.Z. - 7 mar 2001 treated with concentrated hydrochloric acid (38.56 ml) and the resultant mixture was concentrated under vacuum.

Acetone (1480 ml) was then added over 15 minutes and the suspension stirred for 1 hour before filtering off the product. The solid was then slurried with acetone (ca. 500 ml), refiltered and dried at 60°C in vacuo to give the title compound (137.75 g : 87.6%).

A 10 g sample of this material was combined with denatured alcohol (3.5 ml), heated at 60°C for several hours and the solvent then removed In vacuo to afford the product as the desired morphic form.

Crystal Form Purity: the sample of example 2(B) contained above 90% of the anhydrous crystalline form valaciclovir.

The X-ray powder diffraction patterns of the product of example 2(B) are shown in Figures 2 and 3 of the accompanying drawings in which:- Fig 2 is a linear plot X-ray diffractogram; and Fig 3 is a square root plot X-ray diffractogram.

The d spacings and further X-ray diffraction data are shown in Table 2 0 30 40 45 Table 2 Peak No: Angle Peak d Spacing I/Imi (degrees) (counts) pattern (%) (A) 1 3.62 2673 24.40 2 7.21 119 12.26 2 3 8.64 1910 .22 4 9.43 180 9.37 2 .86 2652 8.14 6 12.12 734 7.30 7 13.24 615 6.68 8 8 13.77 106 6.42 1 9 14.50 2333 6.11 31 .14 635 .85 8 11 .89 511 .57 7 12 16.44 2652 .39 13 16.90 1267 .24 17 14 17.33 475 .11 6 18.13 1648 4.89 22 16 .05 2172 4.43 28 17 .56 640 4.32 8 18 21.20 1096 4.19 14 19 21.78 2034 4.08 27 21.90 1384 4.06 18 21 22.66 729 3.92 22 23.94 7621 3.71 100 23 24.39 1624 3.65 21 24 .11 967 3.54 13 .86 2460 3.44 32 26 26.21 5127 3.40 67 27 26.82 1892 3.32 28 26.89 1927 3.31 29 27.19 1429 3.28 19 27.99 1156 3.18 31 28.35 1076 3.15 14 32 28.87 1722 3.09 23 33 28.94 1529 3.08 34 29.62 1274 3.01 17 .56 1673 2.92 22 36 31.30 999 2.86 13 37 32.25 2570 2.77 34 38 33.04 1376 2.71 18 39 34.00 1806 2.63 24 40 34.45 1225 2.60 16 41 .13 1149 2.55 42 36.77 1600 2.44 21 43 38.01 576 2.37 8 44 38.76 729 2.32 45 39.52 524 2.28 7 46 40.70 751 2.22 19- Table 2 Continued Peak No: Angle Peak d Spacing (degrees) (counts) pattern (A) I/Imax (%) 47 48 49 50 51 41.28 41.88 42.47 43.40 44.53 870 686 718 548 729 2.19 2.16 2.13 2.08 2.03 11 9 9 7 10 The diffraction patterns of the product of example 2B were generated on a Phillips PW1800 Automatic X-ray Powder Diffractometer using a scan of 2 to 45 20 with step intervals of 0.02 degrees and an integration time of 4 seconds per step.

Generator settings: 40 KV, 45 mA, Cu alpha 1,2 wavelengths: 1.54060, 1.54439 A; Step size, sample time: 0.020 deg, 4.00 s, 0,005 deg/s; monochromator used: yes; divergence slit: automatic (irradiated sample length: 10.0 mm); peak angle range: 2.000 - 45.000 deg; range in D spacing: 44.1372 -2.01289 A; peak position criterion: top of smoothed data; cryst peak width range: 0.00 - 2.00 deg; minimum peak significance: 0.75 maximum intensity: 7621 cts, 1905.3 cps.

The powder sample was prepared as follows: A 1 gram portion of valaciclovir hydrochloride was transferred to a Retsch 10 ml polystyrol container ref 31-762 containing 2 acrylic balls ref 26-253 and was then ground to a very fine powder using a Retsch MM2 miser mill set at 100% power for five minutes. The ground powder was back loaded into a Philips PW1811/10 sample holder which had been placed inverted on a perfectly smooth surface (e.g. that afforded by a glass plate or a highly polished metal sheet). The powder was then packed into the holder and further powder added and packed until the holder was full. A Philips PW 1811 00 bottom plate was then clamped [h„oE nqw AMENDED into the holder and the entire assembly was then invented before removing the glass/metal plate in an upwards direction to reveal the smooth sample surface whic^n was flush with that of the holder.

The invention is illustrated below in the following examples and the properties of the tablets ^(how in table 3 hereafter.

/ / TENDED into the holder and the entire assembly was then inverted before removing the glass/metal plate in an upwards direction to reveal the smooth sample surface which was flush with that of the holder.

The invention is illustrated below in the following examples and the properties of the tablets shown in table 3 hereafter.

IKTEU.ECTUAL PROPER" OFFICE OF N.Z. ~ 7 mar 2001 Q E 0 Z Si V Z □ i/i C 03 in X m 3 73 c M Ol Examlyl^ 3 4 Ingredients m^. tablet^ kg/ v^Batch w/w mg/ Tablet kg/ Batch w/w mg/ Tablet kg/ Batch w.w Core' (intra granular): k valaciclovir • *2 hydrochloride 576.5 0.9916 576.5 0.9916 82.8 576.5 0.9916 82.3 microcrystalline cellulose (Avicel PHlOl) 70.0 0.1204 .1 70.(T\^ 0.1204 .0 70.0 0.1204 .0 crossporidone 28.0 0.04816 4.0 28.0 0.04816 ' 28.0 0.04816 4.0 povidone K30 povidone K90 22.0 0.03784 3.1 22.0 0.03784 3.2 ^0 0.03784 3.1 extragranular: microJ crystalline cellulose (Avicel PHlOl) \ \ crospovidone - - - - - - - \ " colloidal silicon dioxide (CAB-O-SIL M-5®) 2.0 0.00160 0.3 "X magnesium sterate 4.0 0.0032 0.6 4.0 0.0032 0.6 4.0 0.00320 0.6 \ TOTAL WEIGHT 702.5 1.2028 100.0 696.5 1.198 100.0 700.5 1.2012 100.0 i ro • •• lUxillliple 3 4 Ingredients mg/ Tablet kg/ Batch w/w mg/ Tablet kg/ Batch w/w mg/ Tablet kg/ Batch w.w Cure' (intra granular): valaciclovir hydrochloride 2 576.5 0.9916 82.0 576.5 0.9916 82.8 576.5 0.9916 82.3 inicrocrystalliiic cellulose (Avicel PlllOl) 70.0 0.1204 .1 70.0 0.1204 .0 70.0 0.1204 .0 crospovidone 28.0 0.04816 4.0 28.0 0.04816 4.0 28.0 0.04816 4.0 povidone K.30 povidone K90 22.0 0.03784 3.1 22.0 0.03784 3.2 22.0 0.03784 3.1 extragranular: micro3 crystalline cellulose (Avicel PHlOl) crospovidone - - - - - - - - - colloidal silicon dioxide (CAD-O-SIL M-5®) 2.0 0.00160 0.3 magnesium Tstearate —! 1 4.0 0.0032 0.6 " 4.0 0.00320 0.6 3pTAL |rWI-lGMT 702.5 1.2028 100.0 696.5 1.198 100.0 700.5 1.2012 100.0 I «\) -0 > o m > m z S O r-~"y o N "U /\5) 4© o© Example 6 7 lngte4ients mg/ Tablet kg/ Batch w/w mg/ Tablet kg/ Batch w/w Core' (intra" granular): valaciclovir hydrochloride 2 57&$^ 0.9973 82.3 576.5 0.9973 82.0 microcrystalline cellulose (Avicel PHlOl) \ crossporidone 14.0 0.02422 2.0 0.02422 2.0 povidone K30 povidone K90 22.0 0.03806 3.1 22.0 0"^S506 3.1 extragranular: X •V micro3 crystalline cellulose (Avicel PHlOl) 70.0 0.05600 .0 70.0 0.05600 tflvO crospovidone 14.0 0.11200 2.0 14.0 0.01120 2.0 colloidal silicon dioxide (CAB-O-SIL M-5®) 2.0 0.00160 0.3 magnesium sterate 4.0 0.00320 0.6 4.0 0.00320 0.6 TOTAL WEIGHT 700.5 1.12998 100.0 702.5 1.13158 100.0 * Bulk density 0.6g/cc after 50 taps (anhydrous crystalline form): Karl Fischer water content 1. Core weight per batch : 0.5572kg for examples 3, 4 and 5; 0.4900kg for examples 6 and 7. 2. Factor 1.153 = 100 3. Average particle size about 50fi •• S3 O I-i " Ocl ^ ESs m C 33 O t- C ^ 7S g T-o C3 n -u —-* • i .1 *1 [rl Fxnmplc 6 7 Ingredients mg/ Tablet kg/ Batch w/w mg/ Tablet kg/ Batch w/w Core' (intra granular): valaciclovir * 2 hydrochloride 576.5 0.9973 82.3 576.5 0.9973 82.0 microcrystalline cellulose (Avicel PI1I01) « crospovidone 14.0 0.02422 2.0 14.0 0.02422 2.0 povidone K30 povidone K90 22.0 0.03806 3.1 22.0 0.03806 3.1 extragranular: microJ crystalline cellulose (Avicel PI II01) 70.0 0.05600 .0 70.0 0.05600 .0 crospovidone 14.0 0.11200 2.0 14.0 0.01120 2.0 colloidal silicon dioxide (CAB-O-SIL M-541) 2.0 0.00160 0.3 magnesium stearate 4.0 0.00320 0.6 4.0 0.00320 0.6 TOTAL WRIGHT 700.5 1.12998 100.0 702.5 1.13158 100.0 1 x.. 3.

Hulk (Icnsily 0.6g/cc after 50 taps (anhydrous crystalline form): Karl Fischer water content = 0.4. Core weight per batch : 0.5572kg for examples 3, 4 and 5; 0.4900kg for examples 6 and 7.

Factor 1.153 = 100 Average particle size about 50ji PS PI o m 1 fu to l /\3> i PAGE NOW AMENDED / Example 8 9// Ingredients mg/ tablet w/w mg/ // tablet' '/ . w/w valaciclovir hydrochloride* 615 65.80 65.74 // lactose 205 21.93// / 205 21.91 // mi crocrystalline* cellulose (Avicel PHlOl) (intragranular) 75 / 2 75 8.02 /? povidone K30 19.3 18 1.92 / crospovidone / (intragranular) // /' 18 1.93 18 1.92 / colloidal silicon dioxide (Ae^osil 200) // 0.0 0.0 0.69 0.10 /' magnesium stearate 3.6 0.39 3.6 0.38 / ■^TAL WEIGHT 934.6 100.0 935.5 100 /bulk density 0.45 g/cc after 50 taps (anhydrous crystalline form) 1 Average particle size about 50pi.

/ / PAGE AS AMENDED Example 8 9 Ingredi entrs mg/ tablet w/w mg/ tablet w/w valaciclovir hydrochlori de* 615 65.80 615 65.74 lactose 205 21.93 205 21.91 microcrystalline* cellulose (Avicel PHlOl) (intragranular) 75 8.02 75 8.02 povidone K30 18 19.3 18 1.92 crospovidone (intragranular) 18 1.93 18 1.92 colloidal silicon dioxide (Aerosil 200) 0.0 0.0 0.9 0.10 magnesium stearate 3.5 0.39 3.6 0.38 TOTAL WEIGHT 934.5 100.0 935.5 100 * bulk densiry 0.45 g/cc after 50 taps (anhydrous crystalline form)————-—— . , . jiintellectual property 1 Average particle size about 50u. office of n.z. . ~ 7 MAR 2001 I lr /-\G Example 11 / Ingredients mg/ tablet w/w mg/ tablet/ /w/w i valaciclovir hydrochloride* 580 81.01 J 82.60 / lactose — - / / / microcrystalline cellulose^ (Avicel PHlOl) (intragranular) 70 An - - A / microscrystalline cellulose (extrangranular) - 70.4 .03 / povidone K30 / / 4.89 / povidone K90 / — 21.7 3.09 A crospovidone (intragrap^ilar) 28 3.91 12 1.71 / crospovidone (extragranular) _ 14.1 2.01 / magnesiun/stearate 3.0 0.42 4.0 0.57 / TOT^L WEIGHT 716 100.0 702.2 100.0 1 Average particle size about 50^. density 0.38 g/cc after 50 taps (anhydrous crystalline form) •• 'page as amended 29 a 8 4 a : Example 11 Ingredients mg/ tablet w/w mg/ tablet w/w valaciclovir hydrochloride* 580 81.01 580 82.60 lactose — — — — microcrystalline cellulose'4 (Avicel PHlOl) (intragranular) 70 9.78 - - microcrystalline cellulose: (extragranular) - - 70.4 .03 povidone K30 4.89 — — povidone K90 _ — 21.7 3.09 crospovidone (intragranular) 28 3.91 12 1.71 crospovidone (extragranular) — 14.1 2.01 magnesium stearate 3.0 0.42 4.0 0.57 TOTAL WEIGHT 716 100.0 7022 100.0 * bulk density 0.38 g/cc after 50 taps (anhydrous crystalline form) 2 Average particle size about 50u.

INTELLECTUAL PRO^RTY OFFICE CF N.Z. ~ 7 mar 2001 l^E(SZ!iULD The tablets of the examples were made as disclosed below.

Examples 3 to 7 Step 1. The core ingredients were sifted with a 20 mesh hand screen, and then blended in an appropriately sized V-shell blender for 10 minutes.

Step 2. The blended powders from Step 1 were then granulated in a 10 litre high shear mixer (model-SP1) by adding pure water while mixing. Approximately 11-14% water, w/w of the core ingredients was then added and the mixture massed for 3 to 4% minutes.

Step 3. The granule from Step 2 was dried in a tray (examples 5, 6 and 7) or vacuum (examples 3 and 4) drier (model-SP1) at a temperature of 50°C to an acceptable moisture content of approximately 1.0 to 2.0 % L.O.D.

Step 4. The remaining ingredients were sifted through a 20 mesh screen and added to the core ingredients of step 3, and then the mixture was sifted using a Comil Model 197 AS fitted with a 0.062" screen.

Step 5. The mixture was then blended in an appropriately sized V-shell blender for 5 minutes.

Step 6 The blended granule from Step 5 was compressed on a Manesty Beta Press fitted with capsule shaped tooling, 18.25 mm x 7.14 mm, at a compression weight of approximately 700 mg and a compression force of about 14.5 to 18 kN.

Step 7 The tablets can then optionally be film coated by t 11nGENOW AMENDED 1 using standard methods such as using white concentrate, methylhydroxypropykellulose, titanium dioxide, polyethylene glycol and polysorbate. )lour Hardness (crushing force through the long axis / was measured using a Key hardness tester, Model /HJT-300. Friability (percent weight loss after 100,/^xx inch drops) was measured in accordance with the USP na. 23, 1995, pi981 // at monograph 1216, using an Erweka friability tester, Model // TA-3. Physical properties were measured at comparable compression forces. The disintegration time was measured in accordance with the monograph in/USP 23 (1995) at page 1790.

Examples 8 and 9 // Step 1. The following ingredients as shown were sifted Step 2. with a hand screen. valaciclovir // // Mesh hydrochloride lactose microcrys^gdline Cellulose povidone K30 crospovidone magnesium stearate 60 Mesh colloidal silicon dioxide (CSD) .289 kg 1.763 kg 0.6450 kg 0. 1548 kg 0. 1548 kg 0.03096 kg 0.002598 kg rhe 30 mesh sifted ingredients from Step I were //then blended, excluding the povidone, in a 1 cubic foot V-shell blender for 10 minutes.

Step/3. 1.540 kg of SD3A alcohol (ethanol denatured with 5% methanol) was then mixed with 0.6600 kg of purified water and the screened povidone, 0.1548 using standard methods such as using white colour concentrate, methylhydroxypropy1ce11ulose, titanium dioxide, polyethylene glycol and polysorbate.

Hardness (crushing force through the long axis) was measured using a Key hardness tester, Model HT-300. Friability (percent weight loss after 100, six inch drops) was measured in accordance with the USP no. 23, 1995, pl981 10 at monograph 1216, using an Erweka friability tester, Model TA-3. Physical properties were measured at comparable compression forces. The disintegration time was measured in accordance with the monograph in USP 23 (1995) at page 1790.

Examples 8 and 9 Step 1. The following ingredients as shown were sifted with a hand screen.

Mesh valaciclovir hydrochloride lactose microcrystalline Cellulose povidone K30 crospovidone 60 Mesh magnesium stearate . colloidal silicon dioxide (CSD) .289 kg 1.763 kg 0.6450 kg 0. 1548 kg 0. 1548 kg 0.03096 kg 0.002598 kg Step 2. The 30 mesh sifted ingredients from Step 1 were then blended, excluding the povidone, in a 1 cubic foot V-shell blender for 10 minutes. 3o Step 3. 1.540 kg of SD3A alcohol (ethanol denatured with % methanol) was then mixed with 0.6600 iktellectual propzr'fY purified water and the screened povidon<=, 0©!&5;4Sof N.Z. 7 mar 2001 kg—q-j REG 0 % ,ge now amended rn* kg, was dissolved in 0.6192 kg of the mix^d solvents by hand stirring.

Step 4. The blended powders from Step 2 were ^hen granulated in a 1 cubic foot Littleford Lodige mixer by adding the dissolved povidone while mixing: 1.315 kg of more mixed solvent was added and the mixture massed for sevep minutes total as shown below.

Ploughs 7 min Choppers 6.5 min Step 5. The granule from Step 4 wa^s then dried in a Fluid Bed Dryer (Glatt GPCG5)/with an inlet air temperature of 50°C to/any acceptable moisture content of approximately 1.0 to 3.0% L.O.D.

Step 6. The granule from S>6ep 5 was then sifted using a Fitz Mill Model H fitted with a 30 mesh screen, with knives forward, operating at medium speed.

Step 7. The screened ^magnesium stearate from step 1 was added to the£ granule from Step 6 and blended for 5 minutes /using the blender from Step 2. This was labelled/as example 10 (2.650kg).

Step 8. Part j6f the blended granule from Step 7 was comjpressed on a Manesty Beta Press fitted with oval tooling, 19.1 mm x 10.2 mm, at a compression height of approximately 934.6 mg.

Step 9/f The remainder of the lubricated granule 2.650 kg (from Step 7) was weighed and the sifted CSD from step I added, then dispersed by hand and the mixture blended for 5 minutes in the blender from Step 3. This portion was labelled as Example 11. The mixture was compressed to form tablets.

J^age AS amended Step 4. 10 Step 5.

Step 6.

Step 7.

Step 8.

Step 9. kg, was dissolved in 0.6192 kg of the mixed solvents by hand stirring.

The blended powders from Step 2 were then granulated in a 1 cubic foot Littleford Lodige mixer by adding the dissolved povidone while mixing,; 1.315 kg of more mixed solvent was added and the mixture massed for seven minutes total as shown below.

Ploughs 7 min Choppers 6.5 min The granule from Step 4 was then dried in a Fluid Bed Dryer (Glatt GPCG5) with an inlet air temperature of 50"C to any acceptable moisture content of approximately 1.0 to 3.0% L.O.D.

The granule from Step 5 was then sifted using a Fitz Mill Model M fitted with a 30 mesh screen, with knives forward, operating at medium speed.

The screened magnesium stearate from step 1 was added to the granule from Step 6 and blended for 5 minutes using the blender from Step 2. This was labelled as example 10 (2.650kg).

Part of the blended granule from Step 7 was compressed on a Manesty Beta Press fitted with oval tooling, 19.1 mm x 10.2 mm, at a compression weight of approximately 934.6 mg.

The remainder of the lubricated granule 2.650 kg (from Step 7) was weighed and the sifted CSD from step 1 added, then dispersed by hand and the mixture blended for 5 minutes in the blender from Step 3. This portion was labelled as Ex amp1e _11^ ll'fEB^PROP (Ji-MLC Or N.Z.

The mixture was compressed to form [l:aB:ile,tWAL PR0' { ~ 7 mar 2001 QEfSSEVO WO 96 • * 722082 - PAGE NOW AMEND! Examples 10 and 11 were manufactured in a substantially^ similar manner to Examples 9 an 10 with the following^ exceptions. 2. 3. 4. . 6.

All ingredients were sifted through a 30 mesh sieve. " Drug and intragranular ingredients yfere blended for 10 minutes.

The amounts of water and SD3A aldohol were adjusted for the difference in/Datch size.

Dried granule was milled usii^g a Comil Model 197AS with 0.062" screen.

Example 11 was dried in a /fcray drier. The magnesium stearate was blended for 10 minutes A after 10 minutes prebl^nd of the milled granule and other ingredients/ / jj® page as amended 298846 Examples 10 and 11 were manufactured in a substantially similar manner to Examples 9 and 10 with the following exceptions. 1. All ingredients were sifted through a 20 mesh sieve. 2. Drug and intragranular ingredients were blended for 10 minutes. 3. The amounts • of water and SD3A alcohol were 10 adjusted for the difference in batch size. 4. Dried granule was milled using a Comil Model 197AS with 0.062" screen.

. Example 11 was dried in a tray drier. 6. The magnesium stearate was blended for 10 minutes 15 after 10 minutes preblend of the milled granule and other ingredients.

INTELLECTUAL PROPIRiV OFFICE OF N.Z. ~ 7 mar 2001 &EQ21XJZ® Kxamplc Numbers 3b) 5i 0 5i»r ()a) 61>) 7a) 7I») J!il) Rl>)~ Compression Force (KN) ')!)) I I .256 17.8% 14.746 .343 17.956 I5.65K 17.771 .495 17.896 14.3 31.4 14.7 .7 Selling 6 Selling 7 XAULEJ Hardness (! The tablets of examples 5 and 6, like/zthat of example 3, developed stress cracks after heating. In the tablet of example 3 there was present colloidal silicon dioxide and intragranular microcrystalline cellulose; in example 5 the microcrystalline cellulose was^also intragranular, but there was no colloidal silicon dioxide; and in example 6 again there was no colloidal^ silicon dioxide, but the microcrystalline cellulose^was extragranular.

Surprisingly, however, w#en colloidal silicon dioxide is present and the microcwstalline cellulose is extragranular, there Appears to be synergy which prevents stress cracking. Ttti's effect can be seen in the table of example 7 where there are no stress cracks, and furthermore the hardness and/friability were good. As with the table / / of example 3, the disintegration and ejection force were increased substantially less than would be expected.

'/ As can also/lbe seen from comparative example 8a) the hardness value is very low and the friability fails the US Pharmacopoeia (USP) limit of 1%. Even at the very high compression force used in example 8b), the friability still fails /the USP test.

In/contrast on the addition of about 0.1% w/w of colloidal 35 s/licon dioxide (in example 9a and b), hardness and rriability have dramatically improved. Furthermore the page as amended As can be seen from the results, the tablet of example 4 (which lacks colloidal silicon dioxide and has microcrystalline cellulose intragranularly) broke in half during tumbling, to simulate film coating conditions. The 5 hardness of the tablet is therefore totally unacceptable. On the contrary, when colloidal silicon dioxide was added (example 3) the tablet surprisingly did not break and furthermore the disintegration time and ejection force increased by substantially less than would be expected.

The tablets of examples 5 and 6, like that of example 3, developed stress cracks after heating. In the tablet of example 3 there was present colloidal silicon dioxide and intragranular microcrystalline cellulose; in example 5 the 15 microcrystalline cellulose was also intragranular, but there was no colloidal silicon dioxide; and in example 6 again there was no colloidal silicon dioxide, but the microcrystalline cellulose was extragranular.

Surprisingly, however, when colloidal silicon dioxide is 20 present and the microcrystalline cellulose is extragranular, there appears to be synergy which prevents stress cracking. This effect can be seen in the tablet of example 7 where there are no stress cracks, and furthermore the hardness and friability were good. As with the tablet 25 of example 3, the disintegration and ejection force were increased substantially less than would be expected.

As can also be seen from comparative example 8a) the hardness value is very low and the friability fails the US 30 Pharmacopoeia (USP) limit of 1%. Even at the very high compression force used in example 8b), the friability still fails the USP test.

In contrast on the addition of about 0.1% w/w of colloidal 35 silicon dioxide (in example 9a and b), hardness j-and—^^—^™^-friability have dramatically improved. FurthermoreO.Tfhe of n.z. ~ 7 mar 2c01 ejection force, which was good before the addition of colloidal silicon dioxide is still good, and in fact actually improved on its addition. The disintegration time of the tablets of example 9 is also very satisfactory.

Additionally when the formulation of example 11 is repeated incorporating colloidal silicon dioxide in amounts ranging from 0.05 to 3% w/w, excellent tablets can be consistently produced having a high hardness and low friability value, substantially free of stress-cracks.

The robust tablet formulation of the invention therefore can consistently provide valaciclovir tablets having excellent handling characteristics which are suitable for film coating and which still have an adequate lubricating and disintegration time. 1.

Claims (9)

1. WHAT WE CLAIM IS: 1. A tablet comprising at least about 50% w/w valaciclovir or a salt thereof, a cellulosic filler, a binding agent, a lubricant and about 0.05 to about 3% w/w colloidal silicon dioxide wherein the valaciclovir or a salt thereof is present within the granules of the tablet, the lubricant, silicon dioxide and at least a portion of the cellulosic filler is present extragranularly; wherein the friability of the tablet does not exceed 1%, the hardness is at least 9 kP, and the ejection force does not exceed 1000 Newtons.

2. A tablet as claimed in Claim 1 wherein the colloidal silicon dioxide is present in an amount of about 0.1% to about 0.5% w/w.

3. A tablet as claimed in Claims 1 or 2 wherein the cellulosic filler is present in an amount of about 3% w/w to about 3 0% w/w.

4. A tablet as claimed in Claim 3 wherein the cellullosic filler is present at about 5% to about 15% w/w.

5. A tablet as claimed in Claim 4 wherein the cellulosic filler is present at about 10% w/w.

6. A tablet as claimed in any one of the preceding claims wherein the filler is microcrystalline cellulose.

7. A tablet as claimed in any of the preceding claims, wherein the particle size of cellulosic. f ilfler^ jis intellectual Property Office about 20 to about 3 00yum.. > s FE3 1333 A tablet as claimed in any one of the preceding claims wherein the binding agent is present at about 1 % to about 5 % w/w. A tablet as claimed in any one of the preceding claims wherein the binding agent is methylcellulose or povidone. A tablet as claimed in claim 9 wherein the binding agent is povidone. A tablet as claimed in claim 10 wherein the povidone is povidone K90 grade. A tablet as claimed in any one of the preceding claims wherein the lubricant is present at about 0.1% to about 2.0% w/w. A tablet as claimed in claim 12 wherein the lubricant is a stearate derivative. A tablet as claimed in claim 13 wherein the lubricant is magnesium stearate and is present at about 0. 1% to about 1.0% w/w. A tablet as claimed in any one of the preceding claims wherein the valaciclovir or its salt is present at about 65% to about 85% w/w. A tablet as claimed in any one of the preceding claims comprising valaciclovir hydrochloride. A tablet as claimed in claim 16 wherein the valaciclovir hydrochloride is anhydrous crystalline, form including substantially a d spacing pattern as follows: R £ G P I v f- rs 'ntefectuai Property Office 1 * FEB 1928 of Zealand I A NOW AMENDI -33- d spacing pattern (in Angstroms m. 8 10.20 ± 0.08, 8.10 ± 0.06, 7.27 ± 0.06/ 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ±/0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.11 i0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02,. 2.77 ±,0.02. 1

8. 10 A tablet as claimed in any one mt the preceding claims wherein the tapped /^oulk density of valaciclovir or salt thereof i# about 0.1 to about 0.9g/cc. 1

9. 15 A tablet as claimed in $ny one of the preceding claims which further includes a disintegrating agent present at about/0.5% to about 20% w/w. 20. 20 21, A tablet as claimed in claim 19 wherein the disintegrating ajgfent is a non-ionic disintegrating agent. A tablet a£ claimed in claim 20 wherein the :ing agent is crospovidone present at about 0.5# to about 7% w/w. 25 22. 30 A tablet comprising about 65% to about 85% w/w anhydfrous crystalline valaciclovir hydrochloride inc/uding the d spacing diffraction pattern of cl^im 16, about 1% to about 5% w/w of povidone, out 3% to about 30% w/w of a cellulosic filler, //about 0.5 to about 7% w/w of a non-ionic disintegrating agent, about 0.1% to about 1.0% of a stearate lubricant and about 0.1% to about 0.5% w/w of colloidal silicon dioxide, wherein the valaciclovir hydrochloride is present intragranularly; and wherein the cellulosic filler, stearate lubricant and colloidal silicon , ,R H C E l v E D Intellectual Property Office 1 9 FEB 13£8 [VI :nded -33- d spacing pattern (in Angstroms): 10.20 ± 0.08, 8.10 ± 0.06, 7.27 ± 0.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02,. 2.77 ± 0.02. A tablet as claimed in any one of the preceding claims wherein the tapped bulk density of valaciclovir or salt thereof is about 0.1 to about 0.9g/cc. A tablet as claimed in any one of the preceding claims which further includes a disintegrating agent present at about 0.5% to about 20% w/w. A tablet as claimed in claim 19 wherein the disintegrating agent is a non-ionic disintegrating agent. A tablet as claimed in claim 20 wherein the disintegrating agent is crospovidone present at about 0.5% to about 7% w/w. A tablet comprising about 65% to about 85% w/w anhydrous crystalline valaciclovir hydrochloride including the d spacing diffraction pattern of claim 17, about 1% to about 5% w/w of povidone, about 3% to about 30% w/w of a cellulosic filler, about 0.5 to about 7% w/w of a non-ionic disintegrating agent, about 0.1% to about 1.0% of a stearate lubricant and about 0.1% to about 0.5% w/w of colloidal silicon dioxide, wherein the valaciclovir hydrochloride is._».. present intragranularly; and wherein the 'ce^^o^kS^^1^ filler, stearate lubricant and colloidal, ^i^li^on^ -34- dioxide are present extragranularly 23. A tablet as claimed in any one of Claims 1 to 22 which is film coated. 24. A tablet as claimed in any one of the preceding claims for use in medical therapy. 25. A process for preparing a tablet comprising at least about 50% w/w valaciclovir or a salt thereof, a binding agent, cellulosic filler, a lubricant, and about 0.05 to about 3.0% colloidal silicon dioxide, wherein the friability of the tablet does not exceed 1%, the hardness is at least 9 kP and the ejection force does not exceed 1000N; said process comprising forming granules which include valaciclovir or a salt thereof, then blending the lubricant, colloidal silicon dioxide and at least a portion of the cellulosic filler with said granules, and then compressing the blended mixture to form a tablet. 26. A process according to Claim 25 comprising forming granules by mixing said valaciclovir or salt, optionally a binding agent or a portion thereof, and optionally a portion of the cellulosic filler; granulating with a granulating solution to form granules or dissolving the binding agent or a portion in the granulating solution before adding to valaciclovir; drying the granules; blending the granules with the lubricant, colloidal silicon dioxide, and cellulosic filler or a portion thereof; and then compressing the blended mixture to form a tablet. ' 9 FEB 1P£3 of New Zechnr, ice -35- 8 8 4 27. A process for preparing a tablet comprising at least about 50% w/w valaciclovir or a salt thereof, a binding agent, a lubricant, about 0.05 to about 3% w/w colloidal silicon dioxide, and about 3 to about 30% w/w of a cellulosic filler; wherein the hardness of the tablet is at least 9kP, the friability is not more than 1%, and the ejection force is not more than 1000N; said process comprising forming granules by mixing the valaciclovir or salt, optional binding agent or a portion thereof, and optionally a portion of cellulosic filler; granulating with a granulating solution to form granules or dissolving the binding agent or a portion thereof in the granulating solution before adding to valaciclovir; drying the granules; blending the granules with the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic filler; and then compressing the blended mixture to form a tablet. 28. Use of the combination of 0.05 to 3% w/w colloidal silicon dioxide and cellulosic filler present extragranularly in a tablet including at least 50% w/w intragranular valaciclovir hydrochloride, and extragranular lubricant to prevent stress cracking. 29. A tablet as claimed in claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 9. 30. A process according to claim 25 substantially as hereinbefore described with reference to any one of Examples 1 to 9. . received Intellectual Property Office ' s FEB m of New Zealand